2,6-Dichloro-5-fluoronicotinic acid (=DCFNA) is an important intermediate for preparing quinolonecarboxylic acid derivatives of the naphthyridonecarboxylic acid type which are used for preparing broad-spectrum antibiotics (see EP-A 160 578, EP-A 132 845 and DE-A 35 14 076).
The use of DCFNA as intermediate for pharmaceuticals requires that DCFNA is available in high purity, with good yields and in an economic manner.
Some methods for the production of DCFNA have already been disclosed, in which 2,6-dichloro-5-fluoro-3-cyanopyridine (=DCFN nitrile) undergoes acid hydrolysis. However, these methods do not meet all the requirements mentioned above.
Thus, DCFNA can be obtained according to EP-A 160 578 by hydrolyzing DCFN nitrile in a mixture of acetic acid, water and sulfuric acid. After a reaction time of 16 hours, the required reaction product is isolated in a yield of only 51.5% (see-loc. cit., page 6), which is completely inadequate.
Our own investigations have shown that after a reaction time of 16 hours there was still 39.3% by weight unreacted DCFN nitrile, but 4.7% by weight of the DCFNA had already decomposed, whereas after a reaction time of 32 hours there was still 23.4% by weight unreacted DCFN nitrile, 3.2% by weight of the corresponding carboxamide were present, and the proportion of decomposition products had risen to 8.2% by weight (see comparative example 4). It is accordingly not possible to achieve a significant improvement in the yields by shortening or lengthening the hydrolysis time. Chem. Pharm. Bull. 38, 3211-3217 (1990) describes the hydrolysis of DCFN nitrile initially at 65 to 75xc2x0 C. with 96% by weight sulfuric acid within one hour to the corresponding carboxamide, dilution of the mixture which is then present and contains 99% by weight sulfuric acid by addition of water within 30 minutes at a controlled temperature below 100xc2x0 C. in such a way that the resulting mixture contains about 65% by weight sulfuric acid, and completion of the hydrolysis to DCFNA at 100 to 110xc2x0 C. After renewed dilution, this time to 48% by weight sulfuric acid, crude DCFNA is removed in a yield of 90.5%. However, based on the DCFNA content in the crude product, the yield is only 84.1% (see comparative example 1). The crude product contains 6.6% by weight decomposition products. Even these features make this method uninteresting for industrial application. An additional factor is that the dilution of sulfuric acid with water is very exothermic, so that temperature control is possible if at all only with small reaction batches and slow addition of water, but not with batches on the industrial scale with rapid addition of water. This is therefore only a laboratory method which cannot be transferred to the industrial scale.
Our own experiments have shown that lengthening the metering time for the water for dilution to an extent necessary to make temperature control possible in industrial plants leads to a large increase in the decomposition of DCFNA which has already been formed (see comparative example 2). This leads to a further unacceptable reduction in yield and deterioration in the product.
A modification of this method in which water is metered in isothermally at 0 to 5xc2x0 C. (see WO 98/39298, example 1 c), is likewise of no interest for the industrial scale because a cooling medium at least 20xc2x0 C. cooler would be necessary to remove the heat, which could be provided and handled only with unacceptably high apparatus costs.
In another method (see EP-A 333 020), DCFN nitrile is hydrolyzed in concentrated sulfuric acid within 45 minutes at 75xc2x0 C. to the carboxamide, then, after cooling to 0xc2x0 C., conc. hydrochloric acid is added to the mixture, which is finally heated to boiling for one hour and, after cooling, DCFNA is isolated. The yield is only 19.5%, which is extremely low.
A variant of this method (see WO 98/39298) consists of the carboxamide intermediate being isolated by discharging the reaction mixture onto ice and extraction with a propanol/chloroform mixture, and then being hydrolyzed with conc. hydrochloric acid to DCFNA. Although this increases the yield to 58%, this is still far from satisfactory and the industrial costs necessary for the intermediate isolation and extraction are unreasonably high.
Another method variation described in WO 98/39298 uses the method of diazotizing hydrolysis with nitrous acid to hydrolyze the carboxamide to DCFNA. A large excess of nitrous acid is necessary in this case, and the isolated crude product requires an extremely industrially complicated workup (extraction with an ether, washing of the ether extract with water, extraction of the washed ether phase with sodium carbonate solution and acidification of the enriched sodium carbonate solution to precipitate DCFNA). The use of excess nitrous acid leads to the generation of large amounts of nitrous gases in the reaction and workup, as well as organic phases which contain byproducts and aqueous phases which contain inorganic acids and salts. An ecologically appropriate workup and disposal of all this waste is very complicated and costly. This method is unsuitable for the industrial scale for these reasons too.
Although the methods of WO 98/39298 provide products with purities of up to 98 to 99%, the maximum yield of DCFNA is only 76%. In addition, large reaction volumes are required (for example a 12 liter vessel for a 500 g feed) because otherwise there is occurrence of intermediate states which are difficult to stir.
All the prior art methods for producing DCFNA provide very fine products having average particle sizes in the range from 30 to 75 xcexcm. They are therefore difficult to filter, require long filtration times and, after the filtration, still contain relatively large amounts of mother liquor including the impurities present in the mother liquor.
There is thus still a need for a method for producing DCFNA which can be carried out easily and reliably on the industrial scale, provides the product in good yield, good space yield and good purity, which is economically advantageous and can be carried out with low expenditure on apparatus.
A method for the production of 2,6-dichloro-5-fluoronicotinic acid (DCFNA) by hydrolyzing 2,6-dichloro-5-fluoro-3-cyanopyridine (DCFN nitrile) has now been found and is characterized in that
a) DFCN nitrile is dissolved at 70 to 90xc2x0 C. in sulfuric acid with a concentration of 90 to 99% by weight and hydrolyzed at 70 to 100xc2x0 C. to the corresponding carboxamide,
b) then the reaction mixture is cooled to a temperature in the range from 10 to 65xc2x0 C.,
c) subsequently water is metered in until the concentration of sulfuric acid is 55 to 75% by weight (calculated on the basis of the sulfuric acid employed in stage a) and the water employed in stage c)), keeping the temperature between 30 and 65xc2x0 C. during the addition of the first quarter of the water and keeping the temperature between 50 us 80xc2x0 C. during the addition of the second quarter of the water, and
d) the hydrolysis to DCFNA is completed at 70 to 110xc2x0 C.
DFCN nitrile can be employed in stage a) as such or else in dissolved form. If it is wished to employ it in dissolved form, care must be taken that the solvent does not react with conc. sulfuric acid. Examples of suitable solvents are chlorinated aliphatic compounds. Those preferred have boiling points below 80xc2x0 C., and preferably have boiling points below 70xc2x0 C., because they then distill out of the reaction mixture.
It is also possible to employ the DCFN nitrile dissolved or suspended in phosphorus oxychloride as it results, for example, from its production. It is advantageous to remove some of the phosphorus oxychloride derived from the production of DCFN nitrile, for example by distillation, before mixing with the sulfuric acid.
The dissolving and the hydrolysis in stage a) is preferably carried out at temperatures in the range from 75 to 85xc2x0 C.
If insufficient water for hydrolyzing DCFN nitrile to the corresponding carboxamide has been introduced with the sulfuric acid, further water is added during stage a). The total amount of water (contained in the sulfuric acid plus water added as such where appropriate) for stage a) is preferably 1 to 1.5 mol per mol of DCFN nitrile employed.
The amount of sulfuric acid to be employed in stage a) can be, for example, 1 to 6 times the amount by weight based on DCFN nitrile. The time for the addition of the sulfuric acid and of the DCFN nitrile may vary within wide limits and be, for example, between 0.5 and 10 hours.
The cooling to be carried out in stage b) preferably takes place to temperatures in the range from 20 to 60xc2x0 C.
It is an essential feature of the present invention that stages c) and d) be carried out entirely with increasing temperature. It is advantageous in this connection to combine within the ranges stated in each case high concentrations of sulfuric acid with low temperatures and low concentrations of sulfuric acid with high temperatures, or to select both the concentration of sulfuric acid and the temperature approximately from the middle of the ranges indicated in each case.
The water to be added in stage c) can be metered in various ways, for example a constant quantity per unit time can be added throughout the addition time. This mode of addition is easy to control. It is also possible for the water to be metered in initially in a smaller quantity per unit time and to change to a larger quantity per unit time during the addition. It is possible in this way where appropriate to shorten the total metering time required, but special care must be taken that the temperature limits to be complied with are not exceeded.
The metering time for the water depends essentially on how quickly the heat which is liberated can be removed while maintaining the required maximum temperatures, and can be, for example, in the range from 1 to 10 hours.
The temperature can be controlled during the addition of the water in a quasi-adiabatical or quasi-isothermal manner or in another manner. A quasi-adiabatic procedure can be such that, before the addition of the water, the reaction mixture is brought to a temperature of, for example, 30 to 40xc2x0 C., where appropriate also to an even lower temperature, for example 10 to 30xc2x0 C., and the heat which is produced is removed so that the reaction mixture heats initially to, for example, 30 to 65xc2x0 C. and later to, for example, 50 to 80xc2x0 C.
An example of a quasi-isothermal procedure is to meter in the total quantity of water at, for example, 50 to 65xc2x0 C.
The quasi-adiabatic and the quasi-isothermal procedure can also be combined, for example, working quasi-adiabatically at the start of the addition of water, for example during addition of the first 10 to 30% by weight of the water, and adding the remaining water in a quasi-isothermal procedure at, for example, 50 to 80xc2x0 C.
Other ways of metering the water to be added are also conceivable.
The hydrolysis to DCFNA is completed at temperatures in the range from 70 to 110xc2x0 C. (=stage d)). At a given acid concentration, the time required for this hydrolysis depends essentially on the temperature. If the sulfuric acid concentration is, for example, 63 to 68% by weight (calculated from the added sulfuric acid and the added water), then 1.5 to 3 hours for example are required at temperatures above 95xc2x0 C., 3 to 8 hours for example at temperatures between 80 and 95xc2x0 C., and up to 48 hours for example at temperatures below 80xc2x0 C., to complete the hydrolysis.
The reaction mixture present after stage d), which frequently already contains precipitated DCFNA, can be worked up for example by initially cooling it, for example, to 10 to 30xc2x0 C., then filtering off the DCFNA present, washing it, for example with water, and drying it.
The method of the invention has a number of surprising advantages. Thus, the yield of DCFNA in it is usually more than 85% of theory, frequently 90% of theory and above. The method is easy to carry out, the carboxamide intermediate need not be isolated, and no organic solvents are required. The product results in high purity, contains less than 1% by weight of decomposition products, frequently even less than 0.5% by weight of decomposition products, and can be used further without further purification. The method is particularly environmentally compatible because no nitrous gases, nor salt-containing wastewater nor polluted organic phases are produced, nor is the manipulation of solvents and other aids particularly complicated. In addition, the method can be carried out in conventional apparatus on the industrial scale without difficulty. The reaction volumes required for the method of the invention are small.
Another advantage of the method of the invention is that the resulting DCFNA is less fine than in prior art methods. For this reason, DCFNA produced according to the invention can be filtered more easily and in a shorter time and, after the filtration, it contains only small amounts of mother liquor.
The DCFNA produced according to the invention has average particle sizes above 80 xcexcm, for example in the range from 90 to 180 xcexcm.
It is exceptionally surprising that this large number of advantages can be achieved with the method of the invention because, as is evident from the stated prior art, several attempts have already been made to produce DCFNA in a satisfactory manner on the industrial scale. Only the method of the invention has now provided a simple and efficient method for producing DCFNA.
The present invention also relates to 2,6-dichloro-5-fluoronicotinic acid containing less than 1% by weight of decomposition products, and 2,6-dichloro-5-fluoronicotinic acid which has an average particle size above 80 xcexcm.